Formaldehyde Metabolism and Formaldehyde-induced Alterations in Glucose and Glutathione Metabolism of Cultured Brain Cells

Abstract

Formaldehyde is an environmental pollutant that is also generated in the body during normal metabolic processes. Interestingly, several pathological conditions are associated with an increase in formaldehyde-generating enzymes in the body. The level of formaldehyde in the brain is elevated with increasing age and in neurodegenerative conditions which may contribute to lowered cognitive functions. Although the neurotoxic potential of formaldehyde is well established, the molecular mechanisms involved remain, to a great extent, obscure. Also, the ability of the different types of brain cells to metabolize formaldehyde has not been reported so far. This thesis investigated the capacity of cultured brain cells to metabolize formaldehyde and studied the effects of a formaldehyde exposure on the glucose and the glutathione metabolism by using primary cultures of cerebellar granule neurons or astrocytes as well as the oligodendroglial cell-line OLN-93 as model systems. These cultured cells were remarkably resistant towards acute toxicity of formaldehyde and expressed the mRNAs for enzymes that are known to be involved in formaldehyde generation and disposal, suggesting that brain cells are able to metabolize this aldehyde. Furthermore, all three types of cultures cleared exogenously applied formaldehyde with almost identical rates, but differed in the extent of the formation of the formaldehyde oxidation product, formate. Since formate is a known inhibitor of the cytochrome c oxidase of the mitochondrial respiratory chain and since the metabolism of formaldehyde involves the important antioxidant glutathione, the effect of an exposure of cultured brain cells to formaldehyde on their glucose and glutathione metabolism was also investigated. Formaldehyde application accelerated the export of glycolysis-derived lactate and induced a rapid multidrug-resistance protein 1-mediated export of glutathione from cultured brain cells. These formaldehyde-induced alterations in metabolic pathways of brain cells may contribute to the known impairments in memory and learning that have been reported for neurodegenerative conditions and for formaldehyde-exposed animals.